This physician-Scientist Award will enable Dr. Fletcher to acquire a broad and thorough training in the fields of experimental cytogenetics and molecular biology. In each phase of the award, these skills will be applied to specific research questions in the field of oncology. Phase I will be conducted under the co-sponsorship of Drs. Cynthia C. Morton and Philip Leder, in the Department of Pathology and Genetics, respectively, at Harvard Medial School. A primary focus of this phase will be to localize the causative gene for nevoid basal cell carcinoma syndrome. During Phase I, Dr. Fletcher will also participate in seminars and courses at Harvard Medical School and at the Jackson Laboratory, and will continue extensive work-in-progress on solid tumor cytogenetics. The solid tumor cytogenetics projects will include: 1) identification of characteristic chromosome rearrangements in specific malignancies; 2) investigation of the diagnostic significance of specific cytogenetic patterns in mesenchymal tumors; and 3) determination of the extent and role of genetic instability in adult malignancies. Dr. Samuel E. Lux, Chief of the Hematology-Oncology Division at The Children's Hospital, Boston, and Dr. STeven J. Burakoff, Chief, Division of Pediatric Oncology, Dana-Fraber Cancer Institute, will co-sponsor Phase II of this award. During Phase II, Dr. Fletcher will establish a laboratory devoted to the cytogenetic and molecular characterization of solid tumors at the Dana-Farber Cancer Institute. This laboratory will utilize cytogenetic findings as a basis for subsequent molecular investigations into the etiologies of solid tumors.